Autoimmune response and its long‐term consequences after exon‐skipping therapy in a Duchenne muscular dystrophy mouse model

Abstract

The progress of antisense‐based therapies using first generation Morpholino oligonucleotides for Duchenne muscular dystrophy (DMD) is expected to partially restore dystrophin expression and may prolong the lifespan of DMD patients. In a recent issue of The Journal of Pathology, a sophisticated study by Vila et al used a dystrophic mouse model of DMD to demonstrate that Morpholino‐induced exon skipping induced dystrophin expression in skeletal muscle and stimulated cell mediated and humoral responses to dystrophin. The study highlights the need to further investigate the autoimmune response against de novo synthesised truncated dystrophin protein and its long‐term consequences after exon‐skipping therapy for DMD. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Emerging Oligonucleotide Therapeutics for Rare Neuromuscular Diseases

“…Long-term treatment with oligonucleotides may provoke immune responses to newly expressed proteins. For instance, restored very high levels of dystrophin induced by exon skipping in a short period resulted in an immune response [ 91 ]. Although such potential contraindications of ASO drugs must be thoroughly investigated in patients with DMD and SMA during post-marketing surveillance, shorter dystrophin isoforms or SMN protein in SMA might induce immune tolerance in patients with DMD and SMA, respectively.…”

Role of Immunoglobulins in Muscular Dystrophies and Inflammatory Myopathies

“…The identification of dystrophin autoantibodies in DMD animal models ( 48 , 107 ) and patients ( 46 , 108 ) and the rising of IIMs-associated antibodies highlighted new pathomechanisms in the field of myology and suggested a possible role of the autoantibody-mediated activation of the complement cascade.…”